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Studies on Fluorinated Pyrimidines

XVI. Metabolism of 5-Fluorouracil-2-C¹⁴ and 5-Fluoro-2'-deoxyuridine-2-C¹⁴ in Cancer Patients^*

Kanai Lal Mukherjee, Judith Boohar, Dorothy Wentland, Fred J. Ansfield and Charles Heidelberger

( McArdle Memorial Laboratory, University of Wisconsin, Madison, Wisconsin)

5-Fluorouracil-2-C¹⁴ (FU) and 5-fluoro-2'-deoxyuridine-2-C¹⁴ (FUDR) were administered to cancer patients by oral, intravenous, intramuscular, and intraperitoneal routes. The radioactivity in the plasma, respiratory CO₂, and urine was measured, and fractionation of radioactive materials on ion-exchange columns into the unchanged drug and the various degradation products was carried out with urines and some acid-soluble extracts of plasma. The level of radioactivity in the plasma was higher for the first 2 hours after intravenous injections of FU-2-C¹⁴ and FUDR-2-C¹⁴ than after administration by any other route. The unchanged drugs persisted longer in urine after intravenous injections than after oral, intramuscular, or intraperitoneal administrations. The excretion of radioactivity as respiratory CO₂ was least after the intravenous injection of FUDR. It was concluded, therefore, that intravenous administration of both drugs is the method of choice in the clinical use of these drugs. There was more degradation of FU injected as a continuous infusion than following rapid intravenous injection, and the opposite was true for FUDR.

One patient, who tolerated large doses of FUDR without toxic manifestations, degraded the drug rapidly; whereas a second patient, who rapidly became toxic to FUDR, degraded the drug at a much slower rate. When the degradation of 3',5'-diacetyl-5-fluoro-2'-deoxyrudine-2-C¹⁴ and FUDR-2-C¹⁴, both given orally to the same patient, was compared, it was found that 5'-monoacetyl-FUDR was present in the urine 24 hours after administration of the diacetyl compound, whereas no unchanged drug was found in the urine after administration of FUDR. After intravenous injections of FU-2-C¹⁴ and FUDR-2-C¹⁴, radioactivity was found in the cerebrospinal fluid. Fractionation of the radioactive compounds demonstrated the presence of unchanged drug in the cerebrospinal fluid.

^* This investigation was supported in part by grant, T-157, from the American Cancer Society.

Fellow of the Damon Runyon Memorial Fund for Cancer Research.

American Cancer Society Professor of Oncology.

Received 6/11/62.